Smoking seems to strongly increase rheumatoid arthritis risk among individuals with genetic susceptibility to the disease, researchers found.

People with the genotype most linked to rheumatoid arthritis risk in Caucasians roughly doubled their already-elevated chances of developing the disease if they smoked (relative risk 8.7 versus 4.8 for nonsmokers), Emeli Lundstrom, of the Karolinska Institutet in Stockholm, and colleagues reported.

Their study, published in the June issue of Arthritis & Rheumatism, revealed interactions with smoking for all distinct allele groups with a shared epitope of amino acid sequences on the DRB1 gene.

This gene has been found to have the strongest ties to the 60% of rheumatoid arthritis cases in which anti-citrullinated protein autoantibodies are detected, the researchers noted.

The shared epitope for DRB1 is involved with antigen binding in the human leukocyte antigen area on the chromosome, and thus may play a role in autoimmune responses characteristic of rheumatoid arthritis.

To determine the gene-environment interaction with smoking - the strongest environmental risk factor for rheumatoid arthritis - Lundstrom’s group analyzed findings from the large, population-based, case-control Epidemiological Investigation of Rheumatoid Arthritis study.

The analysis included 1,319 rheumatoid arthritis patients and 943 age- and sex-matched controls randomly selected from the Swedish national population registry.

Among them, 972 patients and 488 controls tested positive for the shared epitope of interest in the study, with further subtype testing for specific alleles within the DRB1*04 group in 759 of these patients and 328 of the controls.

People who smoked at any time in their lives who had any of the SE alleles from the DRB1*04 group were 8.7 times (95% confidence interval 5.7 to 13.1) more likely to have anti-citrullinated protein antibody-positive rheumatoid arthritis than those who didn’t have any of these alleles.

By comparison, never-smokers with any of these alleles were 4.8 times (95% CI 3.0 to 7.5) more likely to have the same anti-citrullinated protein antibody-positive type of rheumatoid arthritis than those without the alleles.

Smoking even more dramatically boosted risk for those with two of the shared epitope DRB1*04 alleles (RR 31.1 versus 8.7 for never-smokers).

The interaction with smoking remained when the analysis was limited to only the *0401 and *0404 subtype of these *04 alleles, with particularly high risk for ever smokers with double *0401/*0404 alleles (RR 39.6 versus never smokers with neither allele).

The shared epitope alleles DRB1*01 and *10 showed the same interaction with smoking in anti-citrullinated protein antibody-positive rheumatoid arthritis.

“Although the different shared epitope alleles are associated with different magnitudes of increased risk of anti-citrullinated protein antibody-positive rheumatoid arthritis, their interaction with smoking seems to be similar,” the researchers said.

However, for rheumatoid arthritis not positive for anti-citrullinated protein antibodies, none of the alleles was associated with increased risk or interacted significantly with smoking.

Lundstrom’s group noted several hypotheses for how smoking might impact the immune system to increase rheumatoid arthritis risk but noted that they could not rule out a purely genetic association with genes that influence smoking behavior.

Primary source: Arthritis & Rheumatism
Source reference:
Lundström E, et al “Gene-Environment Interaction Between the DRB1 Shared Epitope and Smoking in the Risk of Anti-Citrullinated Protein Antibody-Positive Rheumatoid Arthritis: All Alleles Are Important” Arthritis Rheum 2009; 60:1597-1603.